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Design, synthesis, and preliminary bioactivity evaluation of N 1 ‐hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors
Author(s) -
Wang Xue,
Li Xiaoyang,
Li Jingyao,
Hou Jinning,
Qu Ying,
Yu Chenggong,
He Feng,
Xu Wenfang,
Wu Jingde
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12819
Subject(s) - hela , histone deacetylase , histone , indole test , chemistry , docking (animal) , hdac1 , small molecule , biochemistry , stereochemistry , cell , gene , medicine , nursing
Histone deacetylases inhibitors ( HDACI s) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors ( HDACI s) as potential anticancer agents, a series of N 1 ‐hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one ( IC 50 = 0.074 μ m against HeLa nuclear extract ) and showed higher inhibitory activity than the positive control SAHA ( IC 50 = 0.131 μ m ), which was also verified by further molecular docking studies into active site of HDAC 2. The results of selectivity on the inhibition of HDAC s exhibited 12m being with similar isoform selective profile with PXD 101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACI s.